Is IRF3 p.Pro223= (c.669G>A) pathogenic?

IRF3 p.Pro223= (c.669G>A) is classified Likely benign in IRF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-09-17). Ultra-rare (popmax 0.0149%, nfe); Associated with IRF3-related disorder.

What condition is associated with IRF3 p.Pro223= (c.669G>A)?

IRF3 p.Pro223= (c.669G>A) is associated with IRF3-related disorder (ClinVar).

How common is IRF3 p.Pro223= (c.669G>A) in the general population?

IRF3 p.Pro223= (c.669G>A) is ultra-rare (popmax 0.0149%, nfe) (gnomAD).

IRF3 p.Pro223=

c.669G>A · rs778251209 · VCV3051575

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, nfe)

Conditions

IRF3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11
Overall
CADD	0.165	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0149% European (non-Finnish) · 176/1,180,062 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0116% 187/1,613,824 alleles · ultra-rare exomes 181/1,461,538 · genomes 6/152,286 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0149%	6,705
Remaining individualsnot grpmax-eligible	0.0096%	10,413
South Asian	0.00329%	30,365
East Asian	0.00223%	44,904
Admixed American	0.00167%	60,014

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IRF3
Protein: p.Pro223=
Coding: c.669G>A
MANE Select: NM_001571
dbSNP: rs778251209
Type: single nucleotide variant
Location: chr19:49662261 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 223: the 'mediates interaction with zdhhc11' region; the 'interaction with herc5' region

Full IRF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

IRF3-related disorder

Similar variants

IRF3 p.Pro223Leu Uncertain significance ★ ⚠ same residue
IRF3 p.Gln356Ter Uncertain significance ★ same condition
IRF3 p.Arg276Gln Likely benign same condition
IRF3 p.Asn127Ser Likely benign same condition
IRF3 p.Gly278= Likely benign same condition
IRF3 p.Leu403= Benign same condition
IRF3 p.Arg213Cys Uncertain significance ★★ ⚠ same type
IRF3 p.Arg96Trp Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/irf3-p-pro223 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown